The major goal of the proposed investigations is to study in detail the mechanisms of arterial wall repair in relation to the initial stages of atherogenesis. Since the endothelium provides a relative "barrier" between blood components and other vascular cells, particular emphasis will be placed on in vivo and in vitro studies dealing with the interplay of circulating blood cells and specific serum lipoprotein fractions with this key arterial layer. Humoral and cellular mediators will be examined in both normal and hyperlipemic animals following limited vascular injury by techniques recently developed in this laboratory. Parallel studies will be carried out in vitro in order to evaluate the morphological and biochemical methods, cellular adherence and interaction with the injured endothelial lining under both stationary and flow conditions. Possible roles of complement, coagulation and platelet derived components on endothelial and smooth muscle cell proliferation and migration will be examined in rats, rabbits and primates following selective deendothelialization as well as in spontaneous human lesions. Temporary changes in vascular permeability will be followed by evaluation of specific entrapment of circulating plasma lipoproteins and/or synthetic glycolipids by vascular cells with or without preexisting endothelial injury. The role of vasoactive agents as well as activated leukocytes during repair will be carefully investigated in order to evaluate our working hypothesis that abnormal endothelial repair may result in irreversible arterial damage and accelerated atherogenesis. It is anticipated that the proposed simultaneous examination of vascular cell behavior both in vivo and in vitro should be relevant to our understanding of the metabolism and function of the arterial wall and the pathogenesis of thrombosis and atherosclerosis.